Human respiratory syncytial virus (RSV) is a negative-sense, single-stranded RNA virus and a member of the genus Pneumovirus, family Paramyxoviradae. RSV is the leading cause of viral pneumonia and bronchiolitis in infants under one and is a major cause of hospitalization and fatal respiratory tract disease in these infants. Serious disease can also develop in children with certain underlying illnesses (e.g., immunodeficiencies, congenital heart disease, and bronchopulmonary dysplasia). Virtually all children are infected by age two, and re-infection is common in older children and adults. (Chanock et al., in Viral Infections of Humans, 3rd ed., A. S. Evans, ed., Plenum Press, N.Y. (1989)) In healthy adults, most infections are asymptomatic and are generally confined to mild, upper respiratory tract disease; however, elderly patients and immunocompromised individuals are more likely to have severe and possibly life-threatening infections.
Two major, antigenic subgroups of RSV have been identified, A and B, as well as several different genotypes within each subgroup (Anderson et al., 1985, J. Infect. Dis. 151:626-633; Mufson et al., 1985, J. Gen. Virol. 66:2111-2124). The two antigenic subgroups are approximately 25% antigenically related by reciprocal cross-neutralization analysis. Multiple variants of each subgroup have been found to co-circulate in epidemics which occur annually during late fall, winter, and spring months in temperate climates (Anderson et al., 1991, J. Infect. Dis. 163:687-692). There is evidence that children infected with one of the two major RSV subgroups may be protected against re-infection by the homologous subgroup (Mufson et al., 1987, J. Clin. Microbiol. 26:1595-1597). This, along with evidence that protective immunity will accumulate following repeated infections, suggests that it is feasible to develop an RSV vaccination regiment for infants and young children which would provide sufficient immunity to protect against serious disease and death.
A native RSV genome typically comprises a negative-sense polynucleotide molecule which, through complementary viral mRNAs, encodes eleven species of viral proteins, i.e., the nonstructural species NS1 and NS2, N, P, matrix (M), small hydrophobic (SH), glycoprotein (O), fusion (F), M2(ORF1), M2(ORF2), and L, substantially as described in Mink et al., 1991, Virology 185:615-624; Stec et al., 1991, Virology 183:273-287; and Connors et al., 1995, Virology. 208:478-484.
While an immune prophylaxis, Synagis®, is currently marketed for prevention of RSV-associated diseases in premature birth, high-risk infants, despite decades of research, there is no safe and effective vaccine to combat RSV infection and the associated clinical diseases. Secretory antibodies appear to be most important in protecting the upper respiratory tract, whereas high levels of serum antibodies are thought to have a major role in resistance to RSV infection in the lower respiratory tract. However, purified human immunoglobulin (Ig) preparations suffer from the possibility of transmitting blood-borne viruses, while recombinant Ig preparations are expensive to manufacture.
Early attempts (1966) to vaccinate young children used a parenterally-administered, formalin-inactivated RSV vaccine. Unfortunately, administration of this vaccine in several field trials was shown to be specifically associated with the development of a significantly exacerbated illness following subsequent natural infection with RSV (Kapikian et al, 1968, Am. J Epidemiol. 89:405-421; Kim et al, 1969, Am. J Epidemiol. 89:422-434; Fulginiti et al, 1969, Am. J Epidemiol. 89:435-448; Chin et al; 1969, Am. J Epidemiol. 89:449-463). The reasons why this vaccine enhanced RSV disease are not clear. It has been suggested that this exposure to RSV antigens elicited an abnormal or unbalanced immune response which led to an immunopathological potentiation of natural disease (Kim et al, 1976, Pediatr. Res. 10:75-78; Prince et al, 1986, J. Virol. 57:721-728).
The use of a live-attenuated or live-vectored virus vaccine has several advantages over subunit or inactivated virus vaccines. Live, attenuated virus vaccines can mimic natural viral infection, efficiently triggering the host's immune system, and are more likely than a subunit or inactivated vaccine to give a robust immunity comprising both humoral and cellular components.